LRP4 serves as a coreceptor of agrin.
Neuromuscular junction (NMJ) formation requires agrin, a factor released from motoneurons, and MuSK, a transmembrane tyrosine kinase that is activated by agrin. However, how signal is transduced from agrin to MuSK remains unclear. We report that LRP4, a low-density lipoprotein receptor (LDLR)-related protein, is expressed specifically in myotubes and binds to neuronal agrin. Its expression enables agrin binding and MuSK signaling in cells that otherwise do not respond to agrin. Suppression of LRP4 expression in muscle cells attenuates agrin binding, agrin-induced MuSK tyrosine phosphorylation, and AChR clustering. LRP4 also forms a complex with MuSK in a manner that is stimulated by agrin. Finally, we showed that LRP4 becomes tyrosine-phosphorylated in agrin-stimulated muscle cells. These observations indicate that LRP4 is a coreceptor of agrin that is necessary for MuSK signaling and AChR clustering and identify a potential target protein whose mutation and/or autoimmunization may cause muscular dystrophies.
Zhang
Bin
B
Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
Luo
Shiwen
S
Wang
Qiang
Q
Suzuki
Tatsuo
T
Xiong
Wen C
WC
Mei
Lin
L
D018171:Agrin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006801:Humans; D026502:LDL-Receptor Related Proteins; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding / Q000502:physiology; D011940:Receptor Aggregation / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism
D018171:Agrin; D026502:LDL-Receptor Related Proteins; C116415:Lrp4 protein, mouse; D011950:Receptors, Cholinergic; D011973:Receptors, LDL; D014443:Tyrosine; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases